Barriers, facilitators, perceptions and impact of interventions in implementing antimicrobial stewardship programs in hospitals of low-middle and middle countries: a scoping review

Background Antimicrobial stewardship programs (ASPs) are pivotal components of the World Health Organization's Global Action Plan to combat antimicrobial resistance (AMR). ASPs advocate rational antibiotic usage to enhance patient-centered outcomes. However, existing evidence on ASPs and their determinants is largely limited to well-equipped hospitals in high-income nations. Objective This scoping review aimed to examine the current state of hospital-based ASPs in low- and middle-income countries (LMICs), shedding light on barriers, facilitators, prescribers’ perceptions and practices, and the impact of ASP interventions. Design Scoping review on ASP. Methods Adhering to PRISMA guidelines, we conducted electronic database searches on PubMed, Scopus, and Google Scholar, covering ASP articles published between January 2015 and October 2023. Our review focused on four key domains: barriers to ASP implementation, facilitators for establishing ASP, ASP perceptions and practices of prescribers, and the impact of ASP interventions. Three reviewers separately retrieved relevant data from the included citations using EndNote 21.0. Results Among the 7016 articles searched, 84 met the inclusion criteria, representing 34 LMICs. Notably, 58% (49/84) of these studies were published after 2020. Barriers to ASP implementation, including human-resources shortage, lack of microbiology laboratory support, absence of leadership, and limited governmental support, were reported by 26% (22/84) of the studies. Facilitators for hospital ASP implementation identified in five publications included the availability of antibiotic guidelines, ASP protocol, dedicated multidisciplinary ASP committee, and prompt laboratory support. The majority of the research (63%, 53/84) explored the impacts of ASP intervention on clinical, microbiological, and economic aspects. Key outcomes included increased antibiotic prescription appropriateness, reduced antimicrobial consumption, shorter hospital stays, decreased mortality rate, and reduced antibiotic therapy cost. Conclusions The published data underscores the imperative need for widespread antimicrobial stewardship in LMIC hospital settings. Substantial ASP success can be achieved through increasing human resources, context-specific interventions, the development of accessible antibiotic usage guidelines, and heightened awareness via training and education. Supplementary Information The online version contains supplementary material available at 10.1186/s13756-024-01369-6.


Background
Antimicrobial resistance (AMR) has emerged as one of the top ten global public health threats of the twentyfirst century according to the World Health Organization (WHO) [1,2].In 2019, approximately 1.3 million deaths were directly attributable to AMR [3,4].If no measures are taken, it is projected that by 2050 AMR could lead to the deaths of 10 million people annually, with up to 90% of these fatalities occurring in low-and middle-income countries (LMICs) [4].In addition to the health consequences, AMR also carries significant financial implications at both patient and societal levels.According to a World Bank projection, AMR could reduce gross domestic product (GDP) by 1.1-3.8%by 2050, necessitating an annual investment of US$9 billion to counteract AMR effectively [5,6].
The primary drivers of AMR in LMICs include the absence of antibiotic guidelines to regulate prescribing practices [7], irrational use of antibiotics [8], the financial incentive of prescribers, easy accessibility and 'over the counter access' of antibiotics, self-medication, patient pressure, lack of sanitation, poor infection prevention and control (IPC) practices, and the lack of an antimicrobial stewardship program (ASP) [9].To address AMR, WHO formulated a global action plan (GAP) in 2015 [10] which identified ASP as a cornerstone to curtail the inappropriate use of antibiotics for therapeutic use [11,12].Antibiotic stewardship involves a set of coordinated actions that promote the appropriate use of antimicrobials through evidence-based, multidisciplinary interventions against AMR [12,13].In hospital settings, along with infection control measures, ASPs are considered a fundamental strategy to limit the emergence and escalation of AMR [14], improve clinical outcomes, and reduce healthcare costs by promoting the rational use of antibiotics [15,16].
ASP features may vary [17] but typically include a range of interventions tailored to fit the hospital's infrastructure [18].Stewardship interventions can be categorized as persuasive (education and feedback), structural (introduction of new diagnostic tests to guide antibiotic treatment), enabling (guidelines on antibiotic use), or restrictive (expert approval for the use of certain antibiotics) [2,16,19].The key components identified in successful ASPs include leadership commitment, drug expertise, prescribers' accountability, and orientation training for prescribers [13].Most of the recent evidence on ASP comes from resource-intensive hospitals in highincome countries [20,21], making it uncertain whether these findings apply to resource-constrained hospitals [22,23].
This scoping review aimed to map and summarize published data on ASPs deployed in hospital settings in LMICs.It focuses on sequentially integrating four key domains: barriers to implementing ASP, facilitators to establishing ASP, ASP perceptions and practices of prescribers, and the impact of ASP interventions in LMICs.Prior reviews on LMICs mostly focused on the impact of ASP interventions or the ASP methods most widely employed in hospital settings [10,15,24].The findings from this review would be valuable for key stakeholders and policymakers to get an insight into the common obstacles encountered in hospital settings across LMICs, and the key areas on which they need to focus prior to ASP implementation.The review will also help the stakeholders get an idea of where we stand in terms of prescribers' knowledge and perception of ASP across LMIC.

Search strategy
This scoping review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRISMA-ScR) guidelines [25].We developed a systematic search strategy using keywords and medical subject headings (MeSH) terms to identify relevant articles published between January 2015 and December 2023 in MEDLINE, Scopus, and Google Scholar databases.Our search focused on articles related to ASP published after the WHO GAP Plan on AMR in 2015 [13], as this led to increased hospital-based ASP publications in LMICs [10,24].We only included articles published in the English language.The review encompassed countries classified as low, and lower-middle income, according to the World Bank classification system [26].

Study inclusion criteria
Based on our research questions, we established the following inclusion and exclusion criteria to select relevant articles.
Inclusion criteria Our search strategy employed a combination of first, second, and third-string terms.The first string included keywords such as 'antimicrobial' 'antibiotic' 'antimicrobial resistance' and 'antibiotic resistance.' The second string is composed of keywords related to antimicrobial stewardship, such as 'stewardship' 'formulary restriction' and 'prospective audit.' The third string included the terms 'low-middle income countries' 'less developed countries' 'underdeveloped' and 'developing nation.' These search terms were combined using Boolean operators "OR" or "AND" to refine search results.Detailed search strategies can be found in the supplementary file (Additional file 1: Appendix 1.

Study selection
Three reviewers (MGDH, SAS, IH) conducted a systematic title screening of the databases using the specified keywords.Duplicate records were removed and then imported into a citation management program (EndNote 21.0).IH and SAS independently assessed titles and abstracts, while MGDH reviewed the final list.Subsequently, full texts of potentially relevant articles were obtained and evaluated for eligibility.

Data extraction
We extracted and organized data into four domains listed below: The retrieved data included the name of the first author, year of publication, place of study, study design, setting, type of hospital (public, private, or university), study population, and measured outcomes (Table 1).Barriers to ASP implementation (Domain 1, Table 2) and facilitators for establishing ASP (Domain 2, Table 3) were categorized based on constraints and contributing factors described in the articles.The identified impediments or lack of facilities or resources for ASP implementation from the mentioned studies were assembled in Domain 1 as barriers, whereas the availability of facilities or resources to execute ASP was considered in Domain 2 as facilitators.Physicians' perception and practices related to ASP were categorized into knowledge, attitude, and practices (KAP) (Domain 3, Table 4).The impact of ASP interventions was described into five subcategories (Domain 4, Table 5): (1) antibiotic prescription by prescribers (physicians or pharmacists), (2) antibiotic consumption (defined daily doses or days on therapy), (3) clinical outcomes (e.g., length of hospital stay, in-hospital mortality), (4) microbiological outcomes (multi-drug resistance, bacterial resistance patterns), and (5) economic outcomes (hospital antibiotic procurement cost, cost of antibiotic therapy).Antibiotic prescription refers to the quality of antibiotic use (proportion of prescriptions with inappropriate antibiotic use, inappropriate use without clinical indications, unnecessary double coverage, incorrect frequency, dosage, timing, broad-spectrum and expensive antibiotics when inexpensive and narrowspectrum alternatives were available), which was prescribed by hospital physicians or pharmacists.

Facilitators to establishing ASP
The facilitators of hospital ASP implementation are shown in Table 3.Of the five studies documenting ASP enablers, the availability of antibiotic guidelines based on WHO AWaRe classification and ASP protocols was cited as a facilitator for the hospital's ASP implementation in four studies [29,30,39,43].The establishment of a dedicated multidisciplinary ASP committee [30,36,43] was mentioned as an enabling factor for ASP implementation in three studies.Prompt access to microbiology laboratory facilities with institutional antibiograms [30,36], the presence of electronic health records [36,43], and a restricted antimicrobial list in hospitals [43] were also noted as enablers for stewardship implementation.The hospital antibiogram is a periodic summary of antimicrobial susceptibilities of local bacterial isolates which are used by prescribers to determine local susceptibility rates, monitor antibiotic resistance trends over time within the institution, and compare antibiotic resistance trends between hospitals [36].'Others' facilitating factors included the presence of a guideline for infection prevention and control [39,43], external audits with feedback, and empowerment of pharmacists [36].

Discussion
The purpose of this scoping review was to look into the present state of hospital-based ASPs in low-and middleincome countries (LMICs), providing insight into four major domains in a stepwise manner: the obstacles, enablers, attitudes, and behaviors of prescribers, and the outcomes of ASP interventions.Our review identified a shortage of human resources, and a lack of diagnostic facilities as the most commonly encountered barriers to ASP implementation, while the availability of hospital ASP guidelines and dedicated multidisciplinary teams were found to be facilitators.Additionally, the review revealed a substandard baseline about ASP perception among physicians and found that ASP interventions were successful in improving the rational use of antibiotics, reducing antibiotic consumption, and decreasing hospital antibiotic procurement costs.
Our review identified several challenges to implementing ASP in resource-compromised settings, including inadequate human resources, a lack of laboratory infrastructure, unreliable institutional antibiogram, the absence of national guidelines, minimal funding, and a lack of ASP orientation and training [27-30, 35-37, 43, 44].These findings are in line with a previous review, which documented the presence of substandard microbiology laboratory facilities and unreliable antibiograms [1].Physicians' lack of trust in microbiology findings poses a serious threat, as prescribers may lean toward broad-spectrum empiric therapy based on anecdotal evidence.Regarding the absence of context-based antibiotic guidelines and lack of ASP training, our findings are reinforced by prior reviews which also documented these factors as impediments [1,12,23,111].The absence of guidelines implies that prescribers would be unaware of local AMR patterns, leading to the prescription of broad-spectrum antibiotics and the promotion of AMR.Physicians who lack ASP training may administer antibiotics empirically out of habit, and this insufficient training may result in suboptimal ASP understanding among prescribers.
In terms of facilitators toward ASP implementation, existing hospital ASP protocols or guidelines, including their easy access were cited as facilitating factors [29,30,39,43].The presence of guidelines implies that prescribers have a tool that directs them toward prescribing narrow-spectrum antibiotics.Readily available antibiograms suggest that physicians have a trustworthy source of local, relevant antibiotic patterns, which helps them prescribe antibiotics rationally, instead of resorting to a range of resources.
Studies in our review documented a substandard level of knowledge and familiarity among prescribers with the basic principles of ASP.An inadequate fundamental understanding of ASP and AMR would lead to irrational and improper antimicrobial prescriptions [44].Regarding perceptions toward ASP, studies reported positive perceptions toward ASP, as physicians felt that ASP made them think more carefully about their antibiotic choices, beneficial in terms of reducing AMR, decreasing patient length of stay, and reducing healthcare costs [27,31,[49][50][51][52]58].Our review revealed that prescribers were on board to receive regular monitoring and feedback on rational antibiotic use and recommended tailored ASP training [27,45,52,61].However, a few studies also revealed that physicians were concerned that ASP implementation might lead to a loss in their prescribing autonomy [27,47,52].Despite the overall favorable perceptions, most countries have yet to align with global efforts to combat increasing AMR through stewardship activities.Studies in this review documented that hospitals either did not have any ASP initiatives in place [24,45,50] or had few ASP activities with low compliance levels [44,[53][54][55].This low level of ASP compliance might stem from perceiving AMR as an 'external problem' , with some prescribers having a notion that AMR is developed by inappropriate antibiotic use elsewhere instead of on their premises.
Our review found that ASP interventions achieved improvement in rational antibiotic prescription through dose optimization, antibiotic de-escalation, and a reduction in antibiotic prescriptions.ASP implementation documented a reduction in the consumption of WATCH category antibiotics such as vancomycin, meropenem, aztreonam, ceftriaxone, and RESERVE category antimicrobials like colistin, carbapenems, teicoplanin, in hospital wards and ICUs [46,63,71,77,82,83,[100][101][102].Prior systematic reviews demonstrated a decrease in antibiotic consumption after ASP implementation in the ICUs of hospitals [2,24].This decline in consumption might have been achieved by a combination of factors like revising existing hospital antibiotic policies, compliance with antimicrobial policies, stopping orders at 48 h, de-escalation of empirical antimicrobial therapy, and a curb-on combination therapy [46,63].As observed in the review, there was substantial heterogeneity between studies concerning metrics to quantify antibiotic use and consumption.The consumption metrics used were DDD with different denominators (100 or 1000 patient-days) or Days of therapy/DOT per 100 patient-days or 1000 patient-days.This lack of uniformity makes it difficult to compare, aggregate, and interpret data.While the use of different metrics makes it difficult for an accurate and meaningful comparison, an International multidisciplinary panel recommended the simultaneous use of at least two metrics to quantify antibiotic use in hospital settings.DDDs per 100(0) patient-days and days of therapy per patientdays were identified as the most common metric used in the hospital setting [112].Clinical outcomes such as a decrease in the length of hospital stay (LOS), in-hospital mortality, and a reduction in Clostridioides difficile infections were observed after ASP implementation [46,62,63,69,81,86,102]. Prior systematic reviews also confirmed that stewardship activities resulted in positive clinical outcomes [19,113].These findings imply that ASPs curb needless antibiotic consumption among hospital inpatients, and show a positive impact on microbiological outcomes, such as a reduction in the prevalence of multi-drug resistance [82,83,88] and bacterial resistance [82,83].Though fewer studies reported ASPs' impact on economic outcomes, the studies in this review showed a positive effect on ASP implementation which was reiterated by prior reviews that revealed the beneficial effects of ASPs in terms of cost reduction in clinical settings [15,114].ASPs were able to reduce the needless use of expensive parenteral antibiotics and demonstrated a decrease in the use of high-cost broad-spectrum antibiotics [69,88].These pieces of evidence show that ASPs were successful in accomplishing the core objective of reducing inappropriate antibiotic use and antibiotic costs without compromising clinical outcomes.
Clinical outcomes are essential objectives of ASPs that justify the long-term sustainability of any ASP program.Most of the studies included in our review were unable to meet this expectation.Future ASP initiatives should attempt to include and report microbiological, clinical, and cost-effectiveness outcomes.In this review, barring only four studies [77,103,108,109], none of the other citations had a control group.Owing to the lack of a control group and the non-randomized design of most of the studies, confounding effects would be difficult to control.Since hospital settings can also differ across LMICs, this might also result in confounders affecting the prescribing pattern and patient-centered outcomes.If randomization is difficult to conduct, future ASP attempts should at least try to include a control group to minimize confounding and make the results more definitive.The majority of the studies in this scoping review were single-centered, with almost all of them being conducted in tertiary care centers of urban settings.This limits the generalizability of the review since our findings are in line with a recent review that also found that the majority of ASP studies were conducted in urban areas.[24].Implementation of hospital ASP in rural settings of LMICs might also be more challenging owing to financial and resource constraints.Future efforts should emphasize conducting multi-center trials and if possible in rural settings.
Studies in this review had a short follow-up period ranging from 2 to 6 months [46,65,67,69,72,77,86,102], with some studies having no defined follow-up period [64,91].Shortage of the follow-up period would make it difficult to accurately assess microbiological outcomes such as changes in AMR pattern, hospital re-admission, mortality, and determination of the long-term impact of ASP on antimicrobial cost reductions.Long-term evidence of positive economic outcomes would also help to convince stakeholders and policymakers to invest in the ASP program.Furthermore, the implementation of infection prevention and control (IPC) programs to prevent bacterial infections and infections will be necessary to improve patient safety and healthcare quality [14].This approach is strongly linked to ASP, as co-implemented with IPC measures were successful in curbing AMR [115], and future ASP interventions can integrate basic IPC measures into ASP programs.To implement ASP in a resource-compromised hospital setting, WHO recommends the establishment of a multidisciplinary ASP team, comprising infectious diseases specialists, microbiologists, nurses with IPC expertise, and clinical pharmacists as core members [116].Of the 53 studies reporting stewardship interventions, only five studies documented the involvement of multidisciplinary teams with such composition [39,82,86,92,105].Future ASP efforts should concentrate on forming a more inclusive multidisciplinary team to ensure the long-term sustainability of stewardship activities.
Our scoping review sequentially integrates the four ASP domains of barriers, facilitators, prescriber perceptions and practices, and intervention impact to provide a comprehensive overview of the current state of ASP in LMICs, representing cumulative evidence from almost all LMIC regions except the Caribbean.However, this review has a few limitations.We only included articles published in English due to linguistic constraints, which may have resulted in the exclusion of relevant studies in other languages.Albeit the aforementioned limitation, Indian and Pakistani citations are mostly published in English.In addition, our review included global representation except the Carribean.Additionally, the scope of our review was limited to studies published between 2015 and 2023 and there may be earlier studies that could have provided significant insights.However, since hospital-based ASP articles in LMICs increased following the WHO GAP Plan on AMR in 2015, and we included publication from 2015 onwards, along with the most recent citations, this drawback is negated to a substantial extent.Finally, we did not analyze the possibility of bias for the selected research.We excluded documents such as case studies, commentaries, and expert opinions which have a high potential for bias with weak evidence.

Conclusions
Antimicrobial stewardship programs in LMICs face a range of challenges, including a shortage of human resources, inadequate laboratory infrastructure, limited governmental support, and a lack of national guidelines.However, the availability of hospital ASP guidelines and protocols is a significant facilitator for ASP implementation.Physicians in LMICs generally have a suboptimal level of knowledge and familiarity with antimicrobial stewardship programs, but they hold positive attitudes toward ASP and are willing to receive training and educational sessions.ASP interventions in LMICs have been effective in improving the rational use of antibiotics, leading to reduced antibiotic consumption, improved clinical outcomes, positive microbiological outcomes, and economic benefits.Future efforts should focus on addressing the identified barriers to ASP implementation, involving multidisciplinary teams in stewardship initiatives, and integrating infection prevention and control measures into ASP programs to combat antimicrobial resistance effectively in LMICs.

• Domain 1 :
Barriers to ASP implementation • Domain 2: Facilitators for establishing ASP • Domain 3: ASP perceptions and practices of prescribers (physicians or pharmacists) • Domain 4: Impact of ASP interventions

Fig. 1
Fig. 1 PRISMA flowchart of the selection of studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023

Table
Summary of characteristics of included studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023

Table 2
summarizes the reported barriers to ASP implementation.Of the 22 studies that documented barriers to ASP adoption, 50% (11/22) reported a

Table 2
Barriers to implementing ASP of included studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023

Table 3
Facilitators for implementing ASP of included studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023

Table 4
Physicians' perception and practices on ASP of included studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023

Table 5
Impact of ASP intervention of included studies in the scoping review of antimicrobial stewardship programs in low and middle-income countries, 2015-2023